The performance of docetaxel-loaded solid lipid nanoparticles targeted to
, Lingli Chen
, Wangwen Gu, Yu Gao, Liping Lin, Zhiwen Zhang, Yong Xi, Yaping Li
Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
Received 19 July 2008
Accepted 5 September 2008
Available online 11 October 2008
Human hepatocellular carcinoma (HCC) is one of the major causes of death worldwide. Targeted uptake
of therapeutic agent in the cell-, tissue- or disease-speciﬁc manner represents a potential technology for
the treatment of HCC. A new docetaxel-loaded hepatoma-targeted solid lipid nanoparticle (tSLN) was
designed and prepared with galactosylated dioleoylphosphatidyl ethanolamine. The cellular cytotoxicity,
cellular uptake, subcellular localization, in vivo toxicity, therapeutic effect, biodistribution and histology
of tSLNs were investigated. The tSLNs showed the particle size about 120 n
with encapsulation efﬁ-
ciency >90%, a low burst effect within the ﬁrst day and a sustained release for the next 29 days in vitro.
Cytotoxicity of tSLNs against hepatocellular carcinoma cell line BEL7402 was superior to Taxotere
non-targeted SLNs (nSLNs). The tSLNs also showed better tolerant and antitumor efﬁcacy in murine
model bearing hepatoma compared with Taxotere
or nSLNs. The studies on cellular uptake and bio-
distribution indicated that the better antitumor efﬁcacy of tSLNs was attributed to both the increased
accumulation of drug in tumor and more cellular uptake by hepatoma cells. The histology demonstrated
that tSLNs had no detrimental effect on both healthy liver and liver with ﬁbrosis. These results implied
that this targeted nanocarrier of docetaxel could enhance its antitumor effect in vivo with low systemic
toxicity for the treatment of locally advanced and metastatic HCC.
Ó 2008 Elsevier Ltd. All rights reserved.
Primary liver cancer is a major health problem worldwide.
Hepatocellular carcinoma (HCC) is the ﬁfth most common
neoplasm in the world and the third most common cause of cancer-
related death . Treatments of HCC are conventionally divided
into curative and palliative. Surgical resection is the major curative
technique, but it is very limited for patients with multiple or
metastatic tumors . Therefore, it is of great importance to search
for effective chemotherapeutic agents to improve the survival rate
of patients with advanced or recurrent HCC after surgical
Docetaxel is a new taxoid, structurally similar to paclitaxel, but
more effective as inhibitor of microtubule depolymerization .
Docetaxel combined with some chemotherapeutic drugs showed
high anticancer efﬁcacy in patients with breast, pancreatic, gastric
and urothelial carcinomas [4–7]. Although docetaxel produced
profound effects on several hepatocellular carcinoma cells in vitro,
the clinical test didn’t show satisfactory effect in patients with
advanced HCC and liver cirrhosis, mainly due to that docetaxel
lacks tissue and cell speciﬁcity [8–10]. As a result, a drug delivery
system targeted to the liver, especially hepatocellular carcinoma
cells, represents an attractive prospect for future therapy.
Nanoparticles can be delivered to speciﬁc sites by size-depen-
dent passive targeting . It has been reported that nanoparticles
injected intravenously are taken up by the liver after only a few
minutes due to the opsonization process . To obtain higher
selectivity and enhance the uptake of nanoparticles into the target
cells, active targeting could be an effective approach and could be
achieved by modifying the nanoparticles with a ligand that can
bind to the asialoglycoprotein (ASGP) receptor, which is highly
expressed on the surface of several human hepatoma cell lines.
Galactosylation on particle surface can facilitate binding of particle
with ASGP receptors and subsequent uptake into hepatoma cells
We postulated that docetaxel-loaded nanoparticles targeting to
hepatoma cells could bring about enhanced cytotoxicity and anti-
tumor efﬁcacy with better tolerance in vivo for treatment of HCC.
To validate the hypothesis, in this work, we designed docetaxel-
loaded solid lipid nanoparticles (SLNs), which mainly consisted
of biodegradable and biocompatible components-egg yolk
Corresponding author. Tel./fax: þ86 21 5080 6820.
E-mail address: email@example.com (Y. Li).
These authors contributed equally.
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journal homepage: www.elsevier.com/locate/biomaterials
0142-9612/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
Biomaterials 30 (2009) 226–232